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In vitro and in vivo metabolism of psilocybin’s active metabolite psilocin

Jan Thomann, Oliver V Stoeckmann, Deborah Rudin, Patrick Vizeli, Urs Duthaler, Karolina E. Kolaczynska, Marius C. Hoener, Christopher R. Pryce, Franz X. Vollenweider, Matthias E. Liechti

Frontiers in Pharmacology April 29, 2024 DOI: 10.3389/fphar.2024.1391689 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics In vitro and in vivo study Peer reviewed
Population Male C57BL/6J mice and human plasma samples
Intervention Psilocybin
Topics Psilocybin
Keywords Metabolite Glucuronidation Cytochrome p450 In vivo Biochemistry In vitro Cyp3a4 Cyp2d6 Drug metabolism Microsome Pharmacology
Citations 52
Key points MAO-A, CYP2D6, and CYP3A4 are involved in psilocin's metabolism, and putative norpsilocin and oxidized psilocin were newly identified.

Abstract

In vivo , psilocybin is rapidly dephosphorylated to psilocin which induces psychedelic effects by interacting with the 5-HT 2A receptor. Psilocin primarily undergoes glucuronidation or conversion to 4-hydroxyindole-3-acetic acid (4-HIAA). Herein, we investigated psilocybin’s metabolic pathways in vitro and in vivo , conducting a thorough analysis of the enzymes involved. Metabolism studies were performed using human liver microsomes (HLM), cytochrome P450 (CYP) enzymes, monoamine oxidase (MAO), and UDP-glucuronosyltransferase (UGT). In vivo , metabolism was examined using male C57BL/6J mice and human plasma samples. Approximately 29% of psilocin was metabolized by HLM, while recombinant CYP2D6 and CYP3A4 enzymes metabolized nearly 100% and 40% of psilocin, respectively. Notably, 4-HIAA and 4-hydroxytryptophol (4-HTP) were detected with HLM but not with recombinant CYPs. MAO-A transformed psilocin into minimal amounts of 4-HIAA and 4-HTP. 4-HTP was only present in vitro . Neither 4-HIAA nor 4-HTP showed relevant interactions at assessed 5-HT receptors. In contrast to in vivo data, UGT1A10 did not extensively metabolize psilocin in vitro . Furthermore, two putative metabolites were observed. N -methyl-4-hydroxytryptamine (norpsilocin) was identified in vitro (CYP2D6) and in mice, while an oxidized metabolite was detected in vitro (CYP2D6) and in humans. However, the CYP2D6 genotype did not influence psilocin plasma concentrations in the investigated study population. In conclusion, MAO-A, CYP2D6, and CYP3A4 are involved in psilocin’s metabolism. The discovery of putative norpsilocin in mice and oxidized psilocin in humans further unravels psilocin’s metabolism. Despite limitations in replicating phase II metabolism in vitro , these findings hold significance for studying drug-drug interactions and advancing research on psilocybin as a therapeutic agent.

Comparable studies

Other preclinical and animal studies on psilocybin, most cited first.

Study Year Design Participants
Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice 2021 Observational cohort
Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice 2021 Experimental study
Psychedelics reopen the social reward learning critical period Mice 2023 Experimental study in mice
Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice 2020 Experimental study with dose-response experiments
Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice 2013 Experimental study

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